Non-Hodgkin's lymphoma (NHL) is the fifth most common type of cancer in the United States. Approximately 300,000 people are currently living with NHL in the U.S. and an estimated 53,900 new cases will occur in 2002. The 5% annual increase in incidence is the fastest for any human cancer. The therapeutic utility of unmodified monoclonal antibodies (mAbs) and radiolabeled mAbs against the B-cell antigen CD20 is demonstrated by the recent FDA approvals of these agents for the treatment of relapse and refractory B-cell NHL. Although response rates are high, complete cures are rare and the median duration of response is only 1-2 years. Consequently, there is an urgent need for new therapies to prevent or combat disease relapse. CD19 is a 95-kD membrane glycoprotein found on nearly all of B-cell lymphomas, chronic lymphocytic leukemias (CLL), and acute lymphoblastic leukemias (ALL). CD19 is not expressed on mature plasma cells, hematopoietic stem cells, or normal tissues outside the B-lineage. The CDI9 protein is not shed into the circulation and is maintained on tumors despite loss of CD20 expression following anti-CD20 therapy. Taken together, the expression profile of CD19 makes it a highly attractive target for immunotherapy of B-cell neoplasms. Our recent studies in mouse models of human lymphoma demonstrated that CD19 offers clear advantages over CD20 as a target for radioimmunotherapies that employ both traditional and highly innovative radionuclides. The profound anti-tumor effects observed in these studies provide compelling proof-of-principle for CD19-directed therapies. However, our studies employed murine CD19 mAbs that have foreseeable limitations for use in humans. A fully human mAb that recognizes CD19 with high affinity and specificity would be an ideal candidate for therapy. We propose development of novel, fully-human anti-CD19 mAbs using mice that are transgenic for the human immunoglobulin gene locus. The mAbs will be evaluated for specificity and anti-tumor properties in vitro in both unlabeled form and when labeled with novel alpha- and beta-emitting therapeutic isotopes. The most promising immunotherapeutic agents will be critically evaluated for their therapeutic potential using the best available animal models of human lymphoma. Success in the project would provide strong impetus to rapidly advance the most promising agents into development for human clinical testing.